The goal of this research project is to establish, . whether incidence of severity of autoimmune diabetes [IDDM] is increasing or decreasing with age by using the RIP-LCMV transgenic mouse model for IDDM. Preliminary findings point towards a decrease in autoimmune disease. . what the mechanism for the expected decrease in autoimmune disease is. Three possibilities will be addressed in detail. One is the change of cytokine profiles secreted by autoreactive lymphocytes topically in the target organ or systematically, the second is a change in numbers and degree of activation with older age and the third is a change in properties/abilities of antigen presentation in the target organ. . whether efficacy of immune-mediated treatment of IDDM either by oral antigen administration or by peripheral administration of antagonistic peptides with altered ligands is increased or decreased in older age and if yes, what the underlying mechanism are (cytokine profiles, autoreactive lymphocytes). . how oral antigens work, specifically whether other antigens from beta- cells are efficient as well and whether the effect is MHC restricted and can be mapped to distinct sequences/epitopes of the antigen. . whether oral antigen administration and peptide therapy can be increased in efficiency. The significance for undertaking these studies lies in the fact that there is a strong need to develop and understand novel treatment possibilities for autoimmune diseases such as IDDM. So far, oral antigen administration and altered peptide ligands have been applied with varying success and the reason(s) in particular for the failure in humans are not clear. Among other factors, it is very important to understand whether and how the age of the treated individuals effects the potential outcome of treatment. This proposal addresses central pathogenetic issues for autoimmune diseases (such as cytokines, APC function, autoreactive lymphocyte activation) and building on these observations will develop a better knowledge of immunotherapy and its potential. The strength lies in the use of our RIP/LCMV model for virus- induced IDDM, which has been developed and very well characterized in this laboratory. Unlike genetically predetermined models, it offers the advantage that the precise time-point for induction of autoimmunity can be defined (viral infection) and that oral treatment as well as prevention of IDDM with antagonistic peptides has been established.